Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation
Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation
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DOI：
10.1073/pnas.0931430100
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发表时间：
2003-05-13
影响因子：
11.1
通讯作者：
Fisher, DE
中科院分区：
文献类型：
--
作者：
Davis, IJ;Hsi, BL;Fisher, DE
MITF、TFE3、TFEB 和 TFEC 组成转录因子家族 (MiT)，调节多个细胞谱系的关键发育途径。与 MYC 一样，MiT 成员是基本的螺旋-环-螺旋-亮氨酸拉链转录因子。 MiT 成员在其 DNA 结合域中几乎具有完美的同源性，并结合共同的 DNA 基序。 TFE3 的易位发生在人类肾细胞癌的特定亚型和肺泡软组织肉瘤中。尽管多个易位伴侣与TFE3融合，但每个易位产物都保留了TFE3的基本螺旋-环-螺旋亮氨酸拉链。我们已经鉴定出由染色体易位 t(6;11)(p21.1;q13) 融合的基因，这是肾肿瘤另一亚类的特征。在两个原发性肿瘤中，我们发现无内含子基因 Alpha 与 TFEB 的第一个内含子（位于 TFEB 起始 ATG 的上游）重排，保留了整个 TFEB 编码序列。荧光原位杂交证实了 TFEB 和 Alpha 均参与了该易位。尽管Alpha启动子驱动该融合基因的表达，但Alpha基因对CIRF没有贡献。虽然 TFE3 通常与肾肿瘤亚群中的伴侣蛋白融合，但我们发现野生型、未融合的 TFE3 在基于细胞的测定中刺激克隆生长，这表明表达失调，而不是 TFEB 或 TFE3 融合体的功能改变，可能会赋予肿瘤特性，这种机制让人想起伯基特淋巴瘤中启动子替换引起的 MYC 激活。因此，α-TFEB 被鉴定为儿科肾肿瘤子集中的融合基因。
MITF, TFE3, TFEB, and TFEC comprise a transcription factor family (MiT) that regulates key developmental pathways in several cell lineages. Like MYC, MiT members are basic helix-loop-helix-leucine zipper transcription factors. MiT members share virtually perfect homology in their DNA binding domains and bind a common DNA motif. Translocations of TFE3 occur in specific subsets of human renal cell carcinomas and in alveolar soft part sarcomas. Although multiple translocation partners are fused to TFE3, each translocation product retains TFE3 's basic helix-loop-helix leucine zipper. We have identified the genes fused by the chromosomal translocation t(6;11)(p21.1;q13), characteristic of another subset of renal neoplasms. In two primary tumors we found that Alpha, an intronless gene, rearranges with the first intron of TFEB, just upstream of TFEB's initiation ATG, preserving the entire TFEB coding sequence. Fluorescence in situ hybridization confirmed the involvement of both TFEB and Alpha in this translocation. Although the Alpha promoter drives expression of this fusion gene, the Alpha gene does not contribute to the CIRF. Whereas TFE3 is typically fused to partner proteins in subsets of renal tumors, we found that wild-type, unfused TFE3 stimulates clonogenic growth in a cell-based assay, suggesting that dysregulated expression, rather than altered function of TFEB or TFE3 fusions, may confer neoplastic properties, a mechanism reminiscent of MYC activation by promoter substitution in Burkitt's lymphoma. Alpha-TFEB is thus identified as a fusion gene in a subset of pediatric renal neoplasms.